Cell death proceeds by one of two mechanisms: necrosis or apoptosis. In necrosis, the cells lyse and cytosolic components are released. The released cytosolic components elicit severe inflammatory responses. Apoptosis does not result in the release of cytosolic contents, as the cell membrane remains intact even though its surface properties may change. Apoptosis may include the break up of cells into apoptotic bodies, spherical pieces of cells in which the membrane still prevents the release of cytosolic contents. Apoptotic cells and apoptotic bodies are removed in the body by phagocytic cells which are believed to recognize the need to remove such cells by the changes in the outer leaflet of the membrane, in which phosphatidylserine is exposed. Apoptosis typically does not provoke inflammatory responses the way necrosis does because in the former case, the cells are removed by phagocytosis before the cytosolic content is released.
Although cells undergoing apoptosis in vitro initially have intact cell membranes, cells in advanced stages of apoptosis can exhibit loss of membrane integrity. This process is sometimes called "secondary necrosis." It can be observed owing to the absence of phagocytic cells, which in vivo would have removed the apoptotic cells and cell fragments before they could become necrotic.
When neoplastic (tumor) cells are present in the body, it is desirable to cause the death of such cells without causing the death of the normal cells which the patient needs to sustain his life. It is desirable to cause the death of neoplastic cells by inducing apoptosis, so that the cytosolic contents of the neoplastic cells are not released.
Antineoplastic drugs have been reported which kill tumor cells by inducing apoptosis. While some of these drugs have been successful in treating some types of cancer, the drugs have also been known to induce severe side effects, such as cytotoxicity to normal cells by interference with basic cellular functions such as protein synthesis or DNA replication. A few inducers of apoptosis in monocytes have been reported. For example, human blood monocytes can undergo apoptosis when cultured in the absence of serum or stimulatory factors (which is impossible to achieve in vivo). Mangan, et al., "Lipopolysaccharide, tumor necrosis factor-.alpha., and IL-1.beta. prevent programmed cell death (apoptosis) in human peripheral blood monocytes," J Immunol 146:1541 (1991). This process takes two to three days for approximately 50% of the monocytes to become apoptotic (Mangan, et al., "IL-4 enhances programmed cell death (apoptosis) in stimulated human monocytes," J Immunol 148:1812 (1992)), and apoptosis can be postponed by lipopolysaccharide (LPS), interleukin (IL)-1, and .alpha.-tumor necrosis factor (TNF.alpha.). In addition, the anti-inflammatory cytokine IL-4 can enhance apoptosis in LPS-stimulated monocytes. Mangan, D. F. and Wahl, S. M., "Differential regulation of human monocyte programmed cell death (apoptosis) by chemotactic factors and pro-inflammatory cytokines," J Immunol 147:3408-3412(1991). Apoptosis has also been induced in several different cell types by the use of a number of cytokines. However, the potential use of cytokines for treatment of cancer in vivo has suffered from drawbacks, since they have been reported to elicit a variety of deleterious effects, including shock, circulatory collapse and death. In addition, the manufacture of cytokines has been to date, complicated and expensive since recombinant technology for manufacturing proteins is not an inexpensive proposition on a large scale basis.
Further adding to the complicated nature of leukemia treatment is the fact that there are many different types of leukemia. In viewing the scheme of hemopoiesis, pluripotent stem cells divide to form either lymphoid stem cells or myeloid stem cells. Lymphocytes are produced from lymphoid stem cells, while monocytes and granulocytes such as neutrophils, eosinophils and basophils are produced from myeloid stem cells. Myeloid stem cells also give rise to erythrocytes and megakaryocytes. Various leukemias resulting from these differentiated cells include lymphocytic leukemia, monocytic leukemia, and myeloid leukemia. Treatment methodologies and prognosis differ depending on the specific type of leukemia.
Particularly difficult to treat are myeloid and monocytic leukemias. Current treatment methods have achieved palliation and not cure. For example, patients having monocytic leukemia are generally thought to have a low cure rate of less than ten percent. A true remission is impossible to achieve because the Ph-positive clone persists in the bone marrow, and intense chemotherapy treatments designed to eliminate or reduce the clone have only provided modest improvements in the length of survival of these patients. Current chemotherapy is designed to keep the patient asymptomatic for long periods of time by maintaining a total white blood count within an acceptable range.
It is, therefore, desirable to find a new agent that could selectively cause apoptosis of monocytic, myeloid, and leukemia cells without causing severe side effects that accompany the administration of traditional chemotherapeutic agents. It has now been found that a known composition, taurolidine, can be used for the induction of apoptosis in monocytic and myeloid cells.